February 9, 2021 - The European Commission has granted a full marketing authorization for fedratinib for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis who have not received JAK inhibitors or who have received ruxolitinib.
The European Commission has granted a full marketing authorization for fedratinib (Inrebic) for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis who have not received JAK inhibitors or who have received ruxolitinib (Jakafi).1
The regulatory decision was based on data from the phase 3 JAKARTA (NCT01437787)2 and phase 2 JAKARTA2 trials (NCT015233171).3
“With today’s European Commission of [fedratinib], patients with myelofibrosis throughout Europe will now have a critical new option for a rare bone marrow disorder that’s seen little progress in several years,” Diane McDowell, MD, vice president of Hematology Global Medical Affairs of Bristol Myers Squibb, stated in a press release. “We’re committed to improving on standards of care for patients living with hard-to-treat blood diseases and are working collaboratively with European member states to make [fedratinib] available to patients as quickly as possible.”
In the double-blind, placebo-controlled, phase 3 JAKARTA trial, investigators examined the efficacy of once-daily doses of oral fedratinib at either 400 mg (n = 96) or 500 mg (n = 97) compared with placebo (n = 96) in a total of 289 patients with intermediate-2 or high-risk primary or secondary myelofibrosis with splenomegaly.
The primary end point of the research was spleen response, specifically a 35% or greater reduction in spleen volume from baseline. An important secondary end point was symptom response, which was identified to be a 50% or greater reduction in total symptom score assessed per the modified Myelofibrosis Symptom Assessment Form.
Results indicated that 37% of patients who were given fedratinib at a dose of 400 mg experienced spleen response versus just 1% of those who received placebo (P <.0001). Fedratinib also improved the Total Symptom Score by at least 50% when evaluated from baseline to the end of cycle 6 in 40% of patients who received the agent at 400 mg compared with 9% of those who were given placebo (P <.0001).
The most frequently reported toxicities in the fedratinib arm included anemia, gastrointestinal symptoms, increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Twenty-one percent of patients who received fedratinib at a daily dose of 400 mg experienced serious toxicities, the most common of which was cardiac failure, which occurred in 5% of patients.
The single-arm, open-label, multicenter, phase 2 JAKARTA-2 trial examined the efficacy of once-daily doses of oral fedratinib at 400 mg in a total of 97 patients with intermediate or high-risk primary or secondary myelofibrosis with splenomegaly who previously received ruxolitinib.
The primary end point of the trial was spleen response, while key secondary end points include symptom response rate, duration of spleen response, safety.
Results showed 55% (95% CI, 44%-66%) of 83 evaluable patients achieved a spleen response with fedratinib, indicating that those who developed resistance to or were intolerant to ruxolitinib could still experience clinical benefit with the agent.
The most common grade 3/4 toxicities reported with fedratinib were anemia (38%) and thrombocytopenia (22%). Nineteen percent of study participants discontinued treatment because of toxicities. Seven deaths were reported on the study, but none of them were determined to be related to the study drug.
In the clinical development program for the drug, which comprised a total of 608 patients, serious and fatal cases of encephalopathy, including Wernicke’s encephalopathy, have been reported. Eight of the patients experienced serious toxicities (1.3%) and 1 case proved to be fatal (0.16%).
“[Fedratinib] showed clinically meaningful reductions in spleen volume and symptoms in patients who progressed on ruxolitinib or who are JAK inhibitor naïve,” Claire Harrison, MD, FRCP, FRCPath, study investigator of JAKARTA and JAKARTA2, and professor of hematology at Guy’s and St. Thomas’ NHS Foundation Trust, added in the release. “Approximately 1 out of every 100,000 people in the European Union will be diagnosed with myelofibrosis each year, and today’s approval provides an important new option for patients who have remained in urgent need of new therapies.”
Previously, in August 2019, the FDA approved fedratinib for use in adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis, including post-polycythemia vera disease or post-essential thrombocythemia disease based on data from JAKARTA and JAKARTA2.